title: Sustained reduction of alloantibody secreting plasma cells and donor specific antibody with proteasome inhibition in mice.
abstract: The long-lived plasma cells, which develop after alloantigen sensitization, produce donor specific alloantibodies (DSAs) that generate a positive serum cross-match and preclude transplantation. Bortezomib, a proteasome inhibitor, is being investigated in clinical desensitization protocols, however preclinical studies in a transplant model are nonexistent. We hypothesized that sustained treatment with only a proteasome inhibitor would eliminate plasma cells and reduce DSA over time. Cardiac allografts were transplanted into murine recipients. Eight weeks after allograft rejection the proteasome inhibitor, bortezomib, was injected intravenously twice weekly for 60 days. Serum alloantibody responses were assayed using flow cross-match. Total and alloreactive plasma cell numbers were enumerated using flow cytometry and ELISPOT. All recipients of cardiac allografts rejected their graft promptly within 16 days and demonstrated alloantibody by flow cross-match. DSA was sustained in the control mice while mice treated with bortezomib had sustained elimination of DSA and a marked reduction in plasma cell population. Also, bortezomib was associated with an increased level of BLyS. Within a murine model, proteasome inhibition can eliminate alloantibody secreting plasma cells, and reduce alloantibody. Cessation of bortezomib is not associated with return of DSA.
authors.affiliation: Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, United States. Electronic address: rrredfield@wisc.edu.
authors.forename: R R
authors.initials: RR
authors.lastname: Redfield
authors.forename: Y
authors.initials: Y
authors.lastname: Lou
authors.forename: E
authors.initials: E
authors.lastname: Rodriguez
authors.forename: S
authors.initials: S
authors.lastname: Rostami
authors.forename: R F
authors.initials: RF
authors.lastname: Parsons
authors.forename: H
authors.initials: H
authors.lastname: Noorchashm
authors.forename: A
authors.initials: A
authors.lastname: Naji
authors.forename: P L
authors.initials: PL
authors.lastname: Abt
mesh_terms: D064591:Allografts; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D016027:Heart Transplantation; D007518:Isoantibodies / Q000097:blood*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D010950:Plasma Cells / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D007518:Isoantibodies; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex
keywords: Bortezomib; Desensitization; Donor specific antibody; Plasma cell; Proteasome inhibition; Solid organ transplantation